Birth prevalence of homocystinuria in Central Europe: frequency and pathogenicity of mutation c.1105C>T (p.R369C) in the cystathionine beta-synthase gene.
OBJECTIVE
To estimate the frequency of the cystathionine beta-synthase deficiency caused by c.1105C>T mutation in Central Europe compared to Norway, and to examine the pathogenicity of the corresponding p.R369C mutant enzyme.


METHODS
Mutation c.1105C>T was analyzed in 600 anonymous Czech newborn blood spots. Catalytic activity and quaternary structure of the p.R369C mutant was evaluated after expression in 2 cellular systems.


RESULTS
Population frequency of the c.1105C>T mutation was 0.005, predicting the birth prevalence of homocystinuria of 1:40000, which increased to 1:15500 in a model including 10 additional mutations. In Escherichia coli the p.R369C mutant misfolded, and its activity was severely reduced, and expression in Chinese hamster ovary cells enabled proper folding with activity decreased to 63% of the wild-type enzyme. This decreased activity was not due to impaired K(m) for both substrates but resulted from V(max) lowered to 55% of the normal cystathionine beta-synthase enzyme.


CONCLUSIONS
The c.1105C>T (p.R369C) allele is common also in the Czech population. Although the p.R369C mutation impairs folding and decreases velocity of the enzymatic reaction, our data are congruent with rather mild clinical phenotype in homozygotes or compound heterozygotes carrying this mutation.
Janosík
Miroslav
M
Institute of Inherited Metabolic Disorders, Charles University in Prague-1st Faculty of Medicine, Prague, Czech Republic.
Sokolová
Jitka
J
Janosíková
Bohumila
B
Krijt
Jakub
J
Klatovská
Veronika
V
Kozich
Viktor
V
D000818:Animals; D016466:CHO Cells / Q000201:enzymology; D006224:Cricetinae; D003412:Cricetulus; D003541:Cystathionine beta-Synthase / Q000235:genetics*; D018153:Czech Republic / Q000453:epidemiology; D004926:Escherichia coli / Q000201:enzymology; D015870:Gene Expression; D005787:Gene Frequency; D005838:Genotype; D006712:Homocystinuria / Q000201:enzymology / Q000453:epidemiology* / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D009154:Mutation / Q000235:genetics*; D015995:Prevalence; D017510:Protein Folding
D003541:Cystathionine beta-Synthase